1. Field of the Invention
The present invention is related to the field of dissociating ligands from the receptors to which they bind. In particular, the present invention relates to dissociating ligands from integrins and thus treating diseases or conditions associated with binding of the ligands.
2. Background Art
Anti-platelet compounds are useful in treating many cardiovascular diseases including myocardial infarction, restenosis, unstable angina and possibly even atherosclerosis. One target for anti-platelet drugs is the platelet surface receptor called GPIIb-IIa. GPIIb-IIIa is an .alpha..beta. heterodimer present on the platelet surface and is the platelet fibrinogen receptor. At wounds or sites of vascular injury, GPIIb-IIIa mediates platelet adhesion and platelet aggregation. The formation of these platelet thrombi halt blood loss. Unfortunately, platelets can also adhere aberrantly to blood vessel walls, particularly at sites of atherosclerotic plaques. These platelet-rich thrombi can cause unstable angina and when activated, can lead to myocardial infarct.
GPIIb-IIa is a member of the integrin protein family of cell adhesion receptors. GPIIb-IIIa is one of the integrins that can bind to the arg-gly-asp (RGD) peptide motif. This peptide motif is found within a number of adhesive proteins and also in several of the ligands for IIb-IIIa. The primary physiologic ligand for GPIIb-IIIa is fibrinogen, a soluble plasma borne protein that contains two RGD motifs.
There is now great interest in developing small molecule antagonists of IIb-IIIa. Many candidate antagonists of IIb-IIIa have been developed. Most of these are structural mimics of RGD. Current understanding of IIb-IIIa indicates that it contains a single ligand binding pocket which can bind to both RGD and to the gamma chain sequence of fibrinogen. Hence, it is believed that antagonists of IIb-IIIa which bind at this single ligand binding site will be efficacious in preventing the formation of platelet aggregates because they will block the association of fibrinogen with IIb-IIIa.
The present invention provides evidence that IIb-IIIa contains at least two ligand binding pockets and that these two sites are interacting (FIG. 2). The present invention also provides evidence that ligands which bind at Ligand Binding Site I can enact the dissociation of ligand that is already pre-bound at Site II. Because of their unique ability to induce the dissociation of fibrinogen from IIb-IIIa, these antagonists are called Integrin-Ligand Dissociators. Furthermore, the present invention demonstrates that Integrin-Ligand Dissociators are able to enact the dissolution of pre-formed platelet aggregates. These findings indicate a novel approach toward anti-platelet therapy that is a strong departure from the current prophylactic strategy of applying antagonist prior to formation of vascular occlusions. Rather, the present invention demonstrates that the Integrin-Ligand Dissociators of this invention can be applied to reverse platelet aggregates that have already formed.